chr3-170360675-G-T

Position:

• chr3-170360675-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005414.5(SKIL):​c.344G>T​(p.Ser115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

Genes affected

SKIL (HGNC:10897): (SKI like proto-oncogene) The protein encoded by this gene is a component of the SMAD pathway, which regulates cell growth and differentiation through transforming growth factor-beta (TGFB). In the absence of ligand, the encoded protein binds to the promoter region of TGFB-responsive genes and recruits a nuclear repressor complex. TGFB signaling causes SMAD3 to enter the nucleus and degrade this protein, allowing these genes to be activated. Four transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIL	NM_005414.5	c.344G>T	p.Ser115Ile	missense_variant	2/7	ENST00000259119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIL	ENST00000259119.9	c.344G>T	p.Ser115Ile	missense_variant	2/7	1	NM_005414.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.344G>T (p.S115I) alteration is located in exon 2 (coding exon 1) of the SKIL gene. This alteration results from a G to T substitution at nucleotide position 344, causing the serine (S) at amino acid position 115 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.54	.;D;.;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.6	.;L;.;L;L
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.011	D;D;T;D;D
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.99, 1.0	.;D;.;D;D
Vest4		0.42, 0.48, 0.36, 0.38
MutPred		0.23		Gain of catalytic residue at S115 (P = 0.0194);Gain of catalytic residue at S115 (P = 0.0194);.;Gain of catalytic residue at S115 (P = 0.0194);Gain of catalytic residue at S115 (P = 0.0194);
MVP		0.98
MPC		0.67
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-170078463;